Primary glomerulonephritis stands as the third most important cause of end-stage renal disease, suggesting that appropriate treatment may not be as effective as intended to be. Moreover, proteinuria, the hallmark of glomerular damage and a prognostic marker of renal damage progression, is frequently resistant to thorough control. In addition, proteinuria may be the common end pathway in which different pathogenetic mechanisms may converge. This explains why immunosuppressive and nonimmunosuppressive approaches are partly not sufficient to halt disease progression. One of the commonest causes of primary glomerulonephritis is mesangioproliferative glomerulonephritis. Among the triggered intracellular pathways involved in mesangial cell proliferation, the mammalian target of rapamycin (mTOR) plays a critical role in cell growth, in turn regulated by many cytokines, disbalanced by the altered glomerulopathy itself. However, when inhibition of mTOR was studied in rodents and in humans with primary glomerulonephritis the results were contradictory. In light of these controversial data, we propose an explanation for these results, to dilucidate under which circumstances mTOR inhibition should be considered to treat glomerular proteinuria and finally to propose mTOR inhibitors to be prospectively assessed in clinical trials in patients with primary mesangioproliferative glomerulonephritis, for which a satisfactory standard immunosuppressive regimen is still pending. 1. Introduction The universal and growing impact of chronic diseases is undoubtedly high. While there has been little attention paid to kidney disease on a public health level, the reality is that many countries hardly bear the costs of providing end-stage renal disease care through renal replacement therapy. According to the latest USRDS report, while the prevalence of diabetes has clearly increased and the prevalence of congestive heart failure has remained stable, the prevalence of chronic kidney disease appears to have declined slightly in 2009, from 15.8 percent to 15.1 percent when calculated with the MDRD-4 formula and from 14.7 percent to 14.5 percent when calculated with the CKD-EPI formula; prevalence estimates of chronic kidney disease in USA in 1988–1994 had been 12.8 and 12 percent, respectively [1]. Obviously, differences in the prevalence estimates may in part differ depending on the criteria and equations employed. Among the most frequent causes of end-stage renal disease, glomerulonephritis ranks third worldwide. Mesangioproliferative glomerulonephritis, mostly IgA nephropathy, is
References
[1]
United States Renal Data System, Annual Data Report, vol. 1, chapter 1, 2011.
[2]
J. Floege, “Evidence-based recommendations for immunosuppression in IgA nephropathy: handle with caution,” Nephrology Dialysis Transplantation, vol. 18, no. 2, pp. 241–245, 2003.
[3]
B. A. Julian and J. Novak, “IgA nephropathy: an update,” Current Opinion in Nephrology and Hypertension, vol. 13, no. 2, pp. 171–179, 2004.
[4]
G. D’Amico, E. Imbasciati, G. Barbiano di Belgiojoso, et al., “Idiopathic IgA mesangial nephropathy. Clinico-histologic study in 374 patients,” Medicine, vol. 64, pp. 49–57, 1985.
[5]
D. Goumenas, M. Ahuja, J. Shortland, and C. Brown, “Can immunosuppressive drugs slow down the progression of IgA nephropathy?” Nephrology Dialysis Transplantation, vol. 10, pp. 1173–1181, 1995.
[6]
E. Alamartine, J. C. Sabatier, C. Guerin, J. M. Berliet, and F. Berthoux, “Prognostic factors in mesangial IgA glomerulonephritis: an extensive study with univariate and multivariate analyses,” American Journal of Kidney Diseases, vol. 18, no. 1, pp. 12–19, 1991.
[7]
O. Bogenschutz, A. Bohle, C. Batz et al., “IgA nephritis: on the importance of morphological and clinical parameters in the long-term prognosis of 239 patients,” American Journal of Nephrology, vol. 10, no. 2, pp. 137–147, 1990.
[8]
J. S. Cameron, “The long-term outcome of glomerular disease,” in Diseases of the Kidney, R. Schrier and C. Gottschalk, Eds., pp. 1914–1916, Little Brown, Boston, Mass, USA, 5th edition, 1993.
[9]
R. Glassock, A. Cohen, and S. Adler, “Primary glomerular disease,” in The Kidney, B. Brenner, Ed., pp. 1414–1421, W.B. Saunders, Philadelphia, Pa, USA, 5th edition, 1995.
[10]
C. Ponticelli and R. Glassock, “Other primary glomerular diseases,” in Primary Glomerular Diseases, C. Ponticelli and R. Glassock, Eds., pp. 453–460, Oxford University Press, Oxford, UK, 2nd edition, 2009.
[11]
W. A. Border and N. A. Noble, “Transforming growth factor β in tissue fibrosis,” New England Journal of Medicine, vol. 331, no. 19, pp. 1286–1292, 1994.
[12]
S. Klahr, G. Schreiner, and I. Ichikawa, “The progression of renal disease,” New England Journal of Medicine, vol. 318, no. 25, pp. 1657–1666, 1988.
[13]
S. Kramer, T. Loof, S. Martini et al., “Mycophenolate mofetil slows progression in anti-thy1-induced chronic renal fibrosis, but is not additive to a high dose of enalapril,” American Journal of Physiology, vol. 289, pp. F359–F368, 2005.
[14]
G. Remuzzi and T. Bertani, “Pathophysiology of progressive nephropathies,” New England Journal of Medicine, vol. 339, no. 20, pp. 1448–1456, 1998.
[15]
G. Wolf and E. Ritz, “Combination therapy with ACE inhibitors and angiotensin II receptor blockers to halt progression of chronic renal disease: pathophysiology and indications,” Kidney International, vol. 67, no. 3, pp. 799–812, 2005.
[16]
J. Floege and F. Eitner, “Current therapy for IgA nephropathy,” Journal of the American Society of Nephrology, vol. 22, pp. 1785–1794, 2011.
[17]
W. Schuler, R. Sedrani, S. Cottens et al., “SDZ RAD, a new rapamycin derivative: pharmacological properties in vitro and in vivo,” Transplantation, vol. 64, no. 1, pp. 36–42, 1997.
[18]
J. Pascual, A. M. Fernandez, R. Marcen, et al., “Conversion to everolimus in a patient with arterial hypertension and recurrent cutaneous neoplasia–a case report,” Nephrology Dialysis Transplantation, vol. 11, supplement 3, pp. iii38–iii41, 2006.
[19]
J. Pascual, “Everolimus in clinical practice—renal transplantation,” Nephrology Dialysis Transplantation, vol. 21, supplement 3, pp. iii18–iii23, 2006.
[20]
B. Nashan, “Review of the proliferation ihibitor everolimus,” Expert Opinion on Investigational Drugs, vol. 11, no. 12, pp. 1845–1857, 2002.
[21]
A. Meyrier, “Treatment of focal segmental glomerulosclerosis,” Expert Opinion on Pharmacotherapy, vol. 6, no. 9, pp. 1539–1549, 2005.
[22]
M. E. Cho, J. K. Hurley, and J. B. Kopp, “Sirolimus therapy of focal segmental glomerulosclerosis is associated with nephrotoxicity,” American Journal of Kidney Diseases, vol. 49, no. 2, pp. 310–317, 2007.
[23]
F. C. Fervenza, P. M. Fitzpatrick, J. Mertz, et al., “Acute rapamycin nephrotoxicity in native kidneys of patients with chronic glomerulopathies,” Nephrology Dialysis Transplantation, vol. 19, pp. 1288–1292, 2004.
[24]
R. Ramadan, D. Faour, H. Awad et al., “Early treatment with everolimus exetrs renoprotective effects in rats with adraimycin-induced nephrotic syndrome,” Nephrology Dialysis Transplantation. In press.
[25]
Y. X. Su, H. C. Deng, M. X. Zhang, J. Long, and Z. G. Peng, “Adiponectin inhibits PDGF-induced mesangial cell proliferation: regulation of mammalian target of rapamycin-mediated survival pathway by adenosine 5-monophosphate-activated protein kinase,” Hormone and Metabolic Research, vol. 44, pp. 21–27, 2012.
[26]
J. Floege, E. Eng, B. A. Young et al., “Infusion of platelet-derived growth factor or basic fibroblast growth factor induces selective glomerular mesangial cell proliferation and matrix accumulation in rats,” Journal of Clinical Investigation, vol. 92, no. 6, pp. 2952–2962, 1993.
[27]
P. Boor, F. Eitner, C. D. Cohen et al., “Patients with IgA nephropathy exhibit high systemic PDGF-DD levels,” Nephrology Dialysis Transplantation, vol. 24, pp. 2755–2762, 2009.
[28]
N. Ouchi, H. Kobayashi, S. Kihara et al., “Adiponectin stimulates angiogenesis by promoting cross-talk between AMP-activated protein kinase and Akt signaling in endothelial cells,” Journal of Biological Chemistry, vol. 279, no. 2, pp. 1304–1309, 2004.
[29]
Y. Hattori, S. Hattori, K. Akimoto et al., “Globular adiponectin activates nuclear factor-κB and activating protein-1 and enhances angiotensin II-induced proliferation in cardiac fibroblasts,” Diabetes, vol. 56, no. 3, pp. 804–808, 2007.
[30]
J. Po？owinczak-Przyby？ek and G. Me？eń-Mucha, “The inhibitory influence of adiponectin on the growth of the murine endothelial cell line HECa 10 in vitro,” Endokrynologia Polska, vol. 60, no. 3, pp. 166–171, 2009.
[31]
Y. Wang, K. S. L. Lam, J. Y. Xu et al., “Adiponectin inhibits cell proliferation by interacting with several growth factors in an oligomerization-dependent manner,” Journal of Biological Chemistry, vol. 280, no. 18, pp. 18341–18347, 2005.
[32]
T. Shimotomai, M. Kakei, T. Narita et al., “Enhanced urinary adiponectin excretion in IgA-nephropathy patients with proteinuria,” Renal Failure, vol. 27, no. 3, pp. 323–328, 2005.
[33]
N. J. Brunskill, “Rapamycin: a new string to the antiproteinuric bow?” Journal of the American Society of Nephrology, vol. 16, no. 7, pp. 1878–1879, 2005.
[34]
Y. Liu, “Rapamycin and chronic kidney disease: beyond the inhibition of inflammation,” Kidney International, vol. 69, no. 11, pp. 1925–1927, 2006.
[35]
D. D. Sarbassov, S. M. Ali, and D. M. Sabatini, “Growing roles for the mTOR pathway,” Current Opinion in Cell Biology, vol. 17, no. 6, pp. 596–603, 2005.
[36]
S. Kr？mer, Y. Wang-Rosenke, V. Scholl et al., “Low-dose mTOR inhibition by rapamycin attenuates progression in anti-thy1-induced chronic glomerulosclerosis of the rat,” American Journal of Physiology, vol. 294, no. 2, pp. F440–F449, 2008.
[37]
H. R. Lock, S. H. Sacks, and M. G. Robson, “Rapamycin at subimmunosuppressive levels inhibits mesangial cell proliferation and extracellular matrix production,” American Journal of Physiology, vol. 292, no. 1, pp. F76–F81, 2007.
[38]
R. G. B. Bonegio, R. Fuhro, Z. Wang et al., “Rapamycin ameliorates proteinuria-associated tubulointerstitial inflammation and fibrosis in experimental membranous nephropathy,” Journal of the American Society of Nephrology, vol. 16, no. 7, pp. 2063–2072, 2005.
[39]
J. K. Chen, J. Chen, E. G. Neilson, and R. C. Harris, “Role of mammalian target of rapamycin signaling in compensatory renal hypertrophy,” Journal of the American Society of Nephrology, vol. 16, no. 5, pp. 1384–1391, 2005.
[40]
F. Diekmann, J. Rovira, J. Carreras et al., “Mammalian target of rapamycin inhibition halts progression of proteinuria in a rat model of reduced renal mass,” Journal of the American Society of Nephrology, vol. 18, pp. 2653–2660, 2007.
[41]
N. Lloberas, J. M. Cruzado, M. Franquesa et al., “Mammalian target of rapamycin pathway blockade slows progression of diabetic kidney disease in rats,” Journal of the American Society of Nephrology, vol. 17, no. 5, pp. 1395–1404, 2006.
[42]
Y. Tao, J. Kim, R. W. Schrier, and C. L. Edelstein, “Rapamycin markedly slows disease progression in a rat model of polycystic kidney disease,” Journal of the American Society of Nephrology, vol. 16, no. 1, pp. 46–51, 2005.
[43]
M. J. Wu, M. C. Wen, Y. T. Chiu, Y. Y. Chiou, K. H. Shu, and M. J. Tang, “Rapamycin attenuates unilateral ureteral obstruction-induced renal fibrosis,” Kidney International, vol. 69, no. 11, pp. 2029–2036, 2006.
[44]
C. Daniel, L. Renders, K. Amann, E. Schulze-Lohoff, I. A. Hauser, and C. Hugo, “Mechanisms of everolimus-induced glomerulosclerosis after glomerular injury in the rat,” American Journal of Transplantation, vol. 5, no. 12, pp. 2849–2861, 2005.
[45]
C. Daniel, R. Ziswiler, B. Frey, M. Pfister, and H. P. Marti, “Proinflammatory effects in experimental mesangial proliferative glomerulonephritis of the immunosuppressive agent SDZ RAD, a rapamycin derivative,” Experimental Nephrology, vol. 8, no. 1, pp. 52–62, 2000.
[46]
V. Eremina, H. J. Baelde, and S. E. Quaggin, “Role of the VEGF-A signaling pathway in the glomerulus: evidence for crosstalk between components of the glomerular filtration barrier,” Nephron Physiology, vol. 106, no. 2, pp. p32–p37, 2007.
[47]
N. Ferrara, H. P. Gerber, and J. LeCouter, “The biology of VEGF and its receptors,” Nature Medicine, vol. 9, no. 6, pp. 669–676, 2003.
[48]
B. F. Schrijvers, A. Flyvbjerg, and A. S. De Vriese, “The role of vascular endothelial growth factor (VEGF) in renal pathophysiology,” Kidney International, vol. 65, no. 6, pp. 2003–2017, 2004.
[49]
E. Chou, I. Suzuma, K. J. Way et al., “Decreased cardiac expression of vascular endothelial growth factor and its receptors in insulin-resistant and diabetic states: a possible explanation for impaired collateral formation in cardiac tissue,” Circulation, vol. 105, no. 3, pp. 373–379, 2002.
[50]
K. M. Chow, C. C. Szeto, F. M. Lai, P. Poon, T. Y. Wong, and P. K. Li, “Genetic polymorphism of vascular endothelial growth factor: impact on progression of IgA nephropathy,” Ren Fail, vol. 28, pp. 15–20, 2006.
[51]
B. Robert, X. Zhao, and D. R. Abrahamson, “Coexpression of neuropilin-1, Flk1, and VEGF164 in developing and mature mouse kidney glomeruli,” American Journal of Physiology, vol. 279, no. 2, pp. F275–F282, 2000.
[52]
K. Noguchi, N. Yoshikawa, S. Ito-Kariya et al., “Activated mesangial cells produce vascular permeability factor in early- stage mesangial proliferative glomerulonephritis,” Journal of the American Society of Nephrology, vol. 9, no. 10, pp. 1815–1825, 1998.
[53]
H. P. Gerber, A. McMurtrey, J. Kowalski et al., “Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol PI3-kinase/Akt signal transduction pathway: requirement for Flk-1/KDR activation,” Journal of Biological Chemistry, vol. 273, no. 46, pp. 30336–30343, 1998.
[54]
J. Karar and A. Maity, “PI3K/AKT/mTORpathwayinangiogenesis,” Frontiers in Molecular Neuroscience, vol. 4, pp. 1–8, 2011.
[55]
J. A. Tumlin, D. Miller, M. Near, S. Selvaraj, R. Hennigar, and A. Guasch, “A prospective, open-label trial of sirolimus in the treatment of focal segmental glomerulosclerosis,” Clinical Journal of the American Society of Nephrology, vol. 1, no. 1, pp. 109–116, 2006.
[56]
G. Tsagalis, E. Psimenou, A. Iliadis, L. Nakopoulou, and A. Laggouranis, “Rapamycin for focal segmental glomerulosclerosis: a report of 3cases,” American Journal of Kidney Diseases, vol. 54, no. 2, pp. 340–344, 2009.
[57]
J. M. Cruzado, R. Poveda, M. Ibernon et al., “Low-dose sirolimus combined with angiotensin-converting enzyme inhibitor and statin stabilizes renal function and reduces glomerular proliferation in poor prognosis IgA nephropathy,” Nephrology Dialysis Transplantation, vol. 26, pp. 3596–3602, 2011.
